eMedicine Specialties > Dermatology > Fungal Infections

Coccidioidomycosis

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Linas Riauba, MD, Assistant Professor of Clinical Medicine, Department of Medicine, Section of Infectious Disease, University Hospital, University of Medicine and Dentistry of New Jersey

Updated: Jun 12, 2009

Introduction

Background

In 1892, Alejandro Posada first defined coccidioidomycosis as a distinct disease. Coccidioidomycosis is caused by Coccidioides immitis, a dimorphic soil fungus native to the San Joaquin Valley of California, southern portions of Arizona, northern portions of Mexico, and scattered areas in Central America and South America.

C immitis propagates both as a saprophyte and as a parasite. In soil, it grows as a mold with branching septate hyphae. When the soil is disturbed, the hyphae fragment, which forms extremely hardy structures called arthroconidia, can become airborne. If inhaled by animals or humans, the arthroconidia can reach the pulmonary alveoli and transform into thick-walled multinucleate spherules, which form septa and produce hundreds to thousands of uninucleate endospores. Each endospore is capable of producing new spherules or mycelia.

Various other eMedicine articles on coccidioidomycosis are as follows:

• Coccidioidomycosis (Emergency Medicine)
• Coccidioidomycosis (Infectious Diseases)
• Coccidioidomycosis (Ophthalmology)
• Coccidioidomycosis (Pediatrics)
• Coccidioidomycosis (Pulmonology)
• Coccidioidomycosis, Thoracic (Radiology)

Pathophysiology

Almost all C immitis infections result from the inhalation of arthroconidia. Infection may be locally controlled, or it may spread within the lungs or via the bloodstream. In rare occurrences, an inoculation of C immitis causes primary cutaneous coccidioidomycosis with lymphatic extension to the regional lymph nodes; these cases resolve without treatment. In 2009, a report alleged transmission of coccidioidomycosis to a human by a cat bite.¹ This occurred in a veterinary assistant who had been bitten on the hand by a cat that was later diagnosed with disseminated disease.

A single C immitis arthroconidium may be sufficient to produce a naturally acquired respiratory infection. The size of the arthroconidium allows it to be deposited in the terminal bronchiole but probably does not allow it to reach the alveolar space by means of direct inhalation. As an arthroconidium transforms into a spherule, the resulting inflammation results in a local pulmonary lesion. Extracts of C immitis organisms react with complement, leading to the release of mediators of chemotaxis for neutrophils.

In some patients, C immitis leaves the lungs to establish disseminated lesions in distant parts of the body. To establish extrapulmonary sites of infection, the fungal elements must move from the bronchiole into the lung parenchyma and enter and leave the vascular space. In some instances, endospores in the macrophages travel through the lymphatics, reaching the bloodstream. This process is reflected in the common finding of infected hilar, peritracheal, and cervical lymph nodes in patients with extrapulmonary coccidioidal infections. T lymphocytes are of paramount importance in controlling C immitis infections.

Frequency

United States

Approximately 25,000 new, clinically evident cases of coccidioidomycosis are reported annually in the United States, with as many as 75 deaths per year resulting from the infection.

C immitis is endemic in the soil in certain regions of the Western Hemisphere, almost all of which are located between latitudes 40° north and 40° south. In the United States, C immitis is endemic in California's Central Valley and in southern parts of Arizona. It also is endemic in certain places in Utah, Nevada, New Mexico, and Texas. New infections frequently occur during the summer months after the soil dries. In Arizona, a second peak of new clinical infections occurs in October, which corresponds to a similar dry period after the summer rains in that region.

Coccidioidomycosis in Arizona increased in incidence from 1990-1995.² The number of reported cases increased from 255 (7 cases per 100,000 population) in 1990 to 623 (14.9 cases per 100,000 population) in 1995.

The number of annually reported coccidioidomycosis cases in California more than tripled from 2000-2006, rising from 2.4 cases to 8 cases per 100,000 population.³ The annual incidence was highest in Kern County (150 cases per 100,000 population), with the hospitalization rate highest among non-Hispanic blacks, increasing from 3 cases to 7.5 cases per 100,000 population.

International

In addition to regions in the United States, other areas in which C immitis has been identified include northern parts of Mexico adjacent to the Sonoran region of Baja California,⁴ Central America (Nicaragua, Honduras, and Guatemala), and South America (Argentina, Columbia, Venezuela, and Paraguay).

Coccidioidomycosis is endemic in Brazil.⁵ A serologic survey of 229 volunteers in northeast Brazil using the immunodiffusion testing method with commercial Coccidioides species antigens detected 15 individuals without a clinical diagnosis of the disease and 2 individuals in treatment for coccidioidomycosis.⁶ Most of the positive results were in men aged 18-65 years who were engaged in armadillo hunting.

Mortality/Morbidity

• Mortality rates of fulminant infection remain high despite appropriate treatment. In recently published data, of patients in Arizona the hospitalized for it, 48 died, and 12 (25%) of these patients had a concurrent diagnosis of human immunodeficiency virus infection.²
• The infection causes as many as 75 deaths per year in the United States.
• This endemic fungal infection of the southwestern United States causes morbidity and mortality among solid organ transplant recipients who reside in or visit the endemic area or who receive organs from donors infected with the fungus.⁷

Race

• Filipinos have the highest risk of dissemination or progressive pneumonitis.
• African Americans, followed by Mexicans, also appear to have an increased risk for disseminated infection, though their risk is lower than that of Filipinos.

Sex

• Pregnant women are more likely to acquire disseminated coccidioidal infection, especially in the third trimester or in the immediate postpartum period.

Clinical

History

• Most C immitis infections in patients who are immunocompetent are asymptomatic or produce only a self-limited upper respiratory tract illness.
• The first symptoms of primary infection usually appear 9-21 days after exposure.
• Weight loss is a common sign, and headache has been noted in as many as 20% of patients, even in the absence of meningeal involvement.
• The triad of fever, erythema nodosum, and erythema multiform may occur. Erythema nodosum and erythema multiform have a strong predilection for female patients. Migratory arthralgias are common.
• Occasionally, coccidioidal pneumonia is present as a diffuse process. This pneumonia can lead to respiratory failure either because of inoculation with a high concentration of the pathogen or because fungi in the bloodstream infiltrate the lung at many sites. The presentation of coccidioidal pneumonia is fulminant, mimicking that of septic shock or bacterial infection, and mortality rates remain high despite appropriate treatment.
• Since early in the HIV epidemic, most AIDS patients with it had overwhelming diffuse pulmonary disease with a high mortality rate.⁸
• Dissemination of coccidioidomycosis is more likely in pregnancy.⁹ Immunologic and hormonal alterations during pregnancy and postpartum may account for the increased frequency and severity of disease during pregnancy.¹⁰

Physical

In patients with newly diagnosed coccidioidal infections, 2 critical assessments are made: (1) an evaluation of the extent of the disease, which is based on a review of the systems and physical examination, and (2) an identification of the risk factors for future complications.

The most common clinical presentation in patients with coccidioidomycosis is acute or subacute pneumonic illness. Findings in patients with new infection include shortness of breath, cough, chest pain, fever, and fatigue.

Other findings may include the following:

• Pulmonary nodules, cavities, and pneumothorax
  • Approximately 5% of pulmonary infections result in the formation of nodules, which may be as large as 6 cm in diameter. Typically, a nodule causes no symptoms but may be indistinguishable from a neoplasm without histologic examination. Occasionally, nodules may liquefy and drain into a bronchus to form a cavity.
  • Pulmonary cavities may be present initially or in later stages of the pulmonary infectious process. Usually, cavities are peripheral and solitary and, with time, develop a distinctive thin wall. Cavities may remain asymptomatic; one half of them close within 2 years. Some cavities are associated with local symptoms of pleuritic pain, cough, or hemoptysis.
    • Mycetoma may develop in the cavities as a result of infection with either mycelia of C immitis or other fungi such as Aspergillus species.
    • The rupture of a peripheral coccidioidal cavity into the pleural space is a complication that is most common in young male patients.
  • Pneumothorax is often present. An air-fluid level in the pleural space is a clue that the process is not a spontaneous pneumothorax.
• Chronic fibrocavitary pneumonia
  • Some patients develop a chronic fibrotic pneumonia process characterized by both pulmonary infiltrates and pulmonary cavitation.
  • Chronic fibrocavitary pneumonia appears to be associated with diabetes mellitus or preexisting pulmonary fibrosis related to cigarette smoking or other causes.
  • Involvement of more than 1 pulmonary lobe is more common.
  • The lesions may cause systemic symptoms, such as fever, night sweats, and weight loss, as well as local symptoms.
• Extrapulmonary dissemination of infection
  • C immitis spreads beyond the lungs in approximately 0.6% of the infections in the general population. Most extrapulmonary disseminated infections are a result of hematogenous spread of the infectious process.
  • Several factors dramatically increase the risk of dissemination: immunodeficiency conditions, including the late stages of HIV infection¹¹ ; chemotherapy; administration of high-dose (>20 mg/d) corticosteroids; and Hodgkin lymphoma. Additionally, men are more likely to develop disseminated infection than women.
  • Supraclavicular and cervical lymphadenopathy are a common presentation and probably is the result of lymphatic drainage from the pulmonary infection site.
  • The skin is the most common site of dissemination.
    • Involvement ranges from superficial maculopapules, keratotic nodules, and verrucous ulcers to subcutaneous fluctuant abscesses.
    • The lesions have a predilection for the nasolabial fold.
    • Erythema nodosum and erythema multiforme may occur; these have a strong predilection for female patients. Erythema nodosum may manifest as painful subcutaneous nodules and are typically located on the lower extremities. Erythema nodosum may be the first sign of systemic disease. Less commonly, erythema multiforme may develop instead of erythema nodosum, resulting in the typical target lesions. The triad of fever, erythema nodosum, and arthralgias is called desert rheumatism.
    • Buot et al reported finding specific cutaneous lesions of coccidioidomycosis during placement of a ventricular cardiac shunt for chronic meningitis.¹²
  • Joint and bone infections can also occur.
    • Joint infections differ from desert rheumatism: The infections in the latter are typically associated with prominent synovial involvement and effusion, whereas the self-limited joint findings associated with early infection are not.
    • The knee is most often affected, though any joint can be involved. Other commonly infected joints include the joints of the hands and wrists, the feet and ankles, and the pelvis. Although the long bones can be affected, infection in the vertebral column is more common. Involvement of multiple vertebral bodies is typical; these infections may coalesce to produce both anterior and posterior abscesses.
    • Infection may be isolated in the synovium, or it may progress to involve the underlying bone as well. Alternatively, the bones may be involved first, with secondary extension into the joint space.
  • Coccidioidal meningitis is the most serious form of disseminated infection. Untreated, it is almost always fatal within 2-3 years of diagnosis. Meningitis usually develops soon after the symptoms of the initial infection appear (average interval, 6 wk to 6 mo). The primary area of involvement is the basilar meninges.
    • Common presenting signs and symptoms include fever, headache, vomiting, altered mental status, and typical laboratory findings (see Procedures).
    • Hydrocephalus is a common complication, especially in children. Cerebral vasculitis and focal intracerebral coccidioidal abscesses are less common complications.

Causes

• Epidemics of coccidioidomycosis have been linked to large-scale soil disturbances caused by storms, earthquakes, and excavations.
• Farmers, ranchers, construction workers, and others engaged in outdoor activities with significant exposure to soil and dust have a high risk of infection by C immitis.
• Most cases are isolated and sporadic.
• Almost all C immitis infections result from arthroconidia inhalation.
  • A single C immitis arthroconidium may be sufficient to produce a naturally acquired respiratory infection.
  • Infection may be local, or it may spread in the lungs or via the bloodstream.
• Chronic fibrocavitary pneumonia appears to be associated with diabetes mellitus or preexisting pulmonary fibrosis related to cigarette smoking or other causes.
• Stagliano et al reported on a case of fomite-transmitted coccidioidomycosis that occurred in an immune-compromised child.¹³

Differential Diagnoses

Other Problems to Be Considered

Rarely, disseminated coccidioidomycosis with cutaneous involvement may clinically mimic a cutaneous T-cell lymphoma.14

Workup

Laboratory Studies

• At microscopic analysis, C immitis spherules can be visualized by staining biopsy samples with hematoxylin and eosin or Gomori methenamine-silver stain. Sputum or bronchoalveolar-lavage samples are stained with hematoxylin and eosin or Papanicolaou stain. The high sensitivity of the staining permits detection of small numbers of spherules. Direct examination of stained specimens of the spherules is more rapid than other methods and may speed the diagnosis.
• Culturing is more sensitive than other methods. C immitis grows well on most mycologic or bacteriologic media within 5-7 days of incubation. Aerobic conditions are required. Culturing procedures for C immitis are tedious and require experienced personnel and special laboratory containment facilities. Do not attempt culturing unless these provisions are in place because of the risk of infecting laboratory personnel with the airborne arthrospores. The recovery of Coccidioides species by culture and confirmation using the AccuProbe nucleic acid hybridization method by GenProbe is a sensitive and specific diagnostic method.¹⁵ The designation of Coccidioides species as a potential agent of bioterrorism mandates strict regulation of their transport and inventory.
• Serologic testing is most frequently used to diagnose primary infections. Most of the available tests are highly specific for an active infectious process. Minimally reactive test results are often diagnostically important and should not be dismissed as insignificant findings. A negative serologic test result does not exclude a coccidioidal infection. The performance of 1 or more serologic tests over the course of 2 months increases the sensitivity, especially for recently acquired C immitis infection.
• With tube precipitation (TP) antibody testing, immunoglobulin M (IgM) is most adept at forming immune precipitants, and these reactions can be detected early after the onset of infection. This test is sometimes called the IgM test. The antigen responsible for this reaction is a polysaccharide from the fungal cell wall. In as many as 95% of patients, TP antibodies are detected at some point within the first 4 weeks after symptoms appear. Within 7 months after the onset of self-limited disease, TP antibodies are detected in less than 5%.
• Complement-fixing (CF) antibody testing may be helpful. Because immunoglobulin G (IgG) is the immunoglobulin that is usually involved in forming immune complexes, this test is sometimes called the IgG test. Compared with TP antibodies, CF antibodies are identified later and persist for longer periods in early coccidioidal infections. CF antibodies can be present in various body fluids, and their detection in the cerebrospinal fluid is especially important in the diagnosis of coccidioidal meningitis. A titer of 1:16 or greater is commonly associated with extrathoracic dissemination. Higher titers reflect more extensive coccidioidal infection, and increasing CF antibody concentrations are associated with a worsening disease process.¹⁶
• Antibodies detected by using the original TP or CF testing can also be detected by means of alternative procedures called immunodiffusion tube precipitation (IDTP) or immunodiffusion complement-fixing (IDCF) tests, respectively. Both tests are at least as sensitive as their original counterparts.
• An enzyme-linked immunoassay for coccidioidal antibodies is commercially available. The test kit enables the specific detection of IgM or IgG antibodies. Positive results are highly sensitive for coccidioidal infection; however, false-positive results are possible, especially with the IgM enzyme immunoassay. Currently, enzyme immunoassay results should be confirmed with IDTP, IDCF, or CF tests before they are considered diagnostic.
• Bialek et al reported on the use of polymerase chain reaction with chemiluminescent DNA probes, targeting multicopy genes, for identifying clinical isolates of Coccidioides species.¹⁷

Imaging Studies

• Chest radiography may be used to detect granulomas and cavities.¹⁸
• In cases with severe headache, magnetic resonance imaging may be required to evaluate possible meningitis.
• Radionuclide bone scanning can be used to assess for bone lesions in the disseminated form of the disease or to evaluate bone pain.

Other Tests

• Skin testing: In current practice, test is available in the United States for assessing the cellular immune response in persons with coccidioidomycosis. Recent data suggest that archived coccidioidin retains its potency and specificity and that in vitro tests of coccidioidal immunity may have utility in the measurement of coccidioidal cellular immunity.
  • A dermal delayed-type hypersensitivity reaction to coccidioidin is highly specific for coccidioidal infection. However, a positive result may not be related to currently acquired disease because, in most persons, this skin test result remains positive for life after infection.
  • Although skin test results are useful for epidemiologic studies, the test has important limitations when it is used as a screening procedure for recent infections with C immitis.
  • In patients in whom coccidioidomycosis is diagnosed with the help of other tests, the results of skin testing may have prognostic significance.
  • With skin testing, the induration of the skin is measured at 24 hours and 48 hours after coccidioidin is injected intradermally. An induration greater than 5 mm is considered reactive. Erythema at the injection site does not aid in the diagnosis of coccidioidomycosis.

Procedures

• Nonhealing skin lesions may need to be evaluated by means of biopsy.
• When patients present with new complaints of focal discomfort or swelling, appropriate imaging methods or biopsy (if necessary) should be performed.
• Lumbar puncture may be required to evaluate the possibility of meningitis in patients with severe headaches.
  • Increased cerebrospinal fluid pressure, increased WBC counts, increased protein levels, and decreased glucose levels are common findings in patients with meningitis.
  • Occasionally, eosinophils are prominent in the cerebrospinal fluid.
• An effusion that develops in a joint can be aspirated to determine the cell counts and for culturing.

Histologic Findings

Cutaneous coccidioidomycosis with verrucous nodules tends to have an overlying hyperplastic epidermis with a dermal granuloma. Characteristic spores may be evident in the granuloma. Caseation necrosis may also be present.

Primary inoculation disease results in a dense, mixed, inflammatory dermal infiltrate with occasional giant cells and the formation of small abscesses. Spores may be evident, though hyphae are less likely to be present.

The occasionally associated erythema nodosum has typical histologic features, with no alterations suggestive of coccidioidomycosis. The same is true of erythema multiforme, which is less commonly linked to coccidioidomycosis.

Treatment

Medical Care

The management of primary respiratory infections resulting from C immitis is controversial because of the lack of prospective controlled trials. For many (if not most) patients, care may involve the periodic reassessment of symptoms and radiographic findings to ensure the resolution of the disease without antifungal treatment. Conversely, some authorities propose treatment in all symptomatic patients. Antifungal therapy should be initiated in the presence of concurrent risk factors (eg, HIV infection, organ transplant, high doses of corticosteroids) or unusually severe infections.

Desired outcomes of treatment include the resolution of signs and symptoms of infection, a reduction of serum concentrations of antibodies to C immitis, and the return of function in the involved organs. Also desirable is the prevention of a relapse of the illness when therapy is discontinued, although current therapy is often unable to achieve this goal.

The 3 components of the management of coccidioidal infections include the following: (1) assessing the need for intervention, (2) selecting the antifungal agents, and (3) selecting the surgical procedures.

The need for intervention, either medical or surgical, should be assessed. The severity of the disease should be determined in each patient. The particular lesion location, signs of adjacent tissue and organ involvement, and signs of disseminated disease should be evaluated. Common indicators of the severity of the disease include the following:

• Weight loss of more than 10%
• Intense night sweats persisting for longer than 3 weeks
• Infiltrates involving more than one half of 1 lung or portions of both lungs
• Prominent or persistent hilar adenopathy
• Concentrations of CF antibody to C immitis in a ratio of more than 1:16, as determined by using a reference method or an equivalent titer
• Failure to develop dermal hypersensitivity to coccidioidal antigens
• An inability to work
• Symptoms that persist for longer than 2 months
• African American, Filipino, or Mexican race

Antifungal agents should be selected for patients who may benefit from treatment. Before antifungal therapy was available, the natural history of initial pulmonary infections resulting from C immitis revealed that these infections spontaneously resolved in at least 95% of patients. To the authors' knowledge, randomized prospective clinical trails of antifungals have not been completed to determine whether drug therapy hastens the resolution of immediate symptoms or prevents subsequent complications.

Although most patients with primary infection recover without therapy, those with severe primary infection should generally receive chemotherapy. Patients with high CF titers require chemotherapy as well. Other criteria in determining the need for chemotherapy include the following:

• Symptoms persisting for longer than 6 weeks
• Prostration
• Extensive, enlarging, or persisting pulmonary involvement
• Persisting precipitins
• Negative skin test result
• Infancy
• Pregnancy (see Special Concerns)
• Debilitation
• Concurrent diseases likely to be adversely affected by coccidioidal infection (eg, diabetes, asthma, emphysema)
• Impairment of immune system
• Filipino, African American, or Hispanic race (see Race)

Once the disease has spread beyond the lungs, chemotherapy is always indicated. Surgical procedure may include the debridement and reconstruction of destructive lesions (see Surgical Care below). An effective vaccine needs to be developed. Dendritic cell – based and other vaccines against Coccidioides infection are being explored.

Surgical Care

The need for surgery is determined by the nature of specific lesions on a case-by-case basis because the manifestations, locations, and severity of progressive forms of coccidioidomycosis vary greatly among patients.

• In some patients, especially those with extensive skeletal or dermal involvement, debridement and drainage of the infected sites may be critical in controlling the infection.
  • A reason for performing this procedure may be that the spherule wall, a strong stimulus for inflammation, cannot be degraded easily or cleared from large coccidioidal lesions by macrophages and other elements of the reticuloendothelial system.
  • Therefore, even if therapy is effective in arresting fungal proliferation, fungal debris that is already present may continue to cause tissue destruction until it is surgically removed.
• Chronic pulmonary cavities respond poorly to antifungal therapy.
  • Bacterial superinfection or hemoptysis due to the development of a fungus ball caused by Aspergillus species or C immitis itself may be complications.
  • Cavitations may be progressive despite chemotherapy. In such cases, surgical resection may be valuable.

Consultations

Consultation with an infectious disease specialist is appropriate, especially in patients with concomitant HIV infection and in patients with CNS involvement.

Medication

In coccidioidomycosis, selection between amphotericin B and azole antifungals is based primarily on the severity of the infectious process, the degree of respiratory compromise in pulmonary infections, or the rate of progression of disseminated infections. Amphotericin B has more rapid onset of action compared with that of azole antifungals; therefore, despite its well-known toxicities, amphotericin B is the preferred initial therapy for patients with respiratory compromise or those whose condition is deteriorating rapidly. No evidence suggests that lipid formulations improve the effectiveness of amphotericin B suspended with deoxycholate. Azole antifungals are often used in patients with chronic disease because the ease of administration and lack of significant toxicities outweigh possible differences in the rates of response. During pregnancy, amphotericin B is the treatment of choice because fluconazole medications, and probably other azole antifungals, are teratogenic.

Patients with mild disease may not require treatment, and those with severe symptoms may experience disseminated disease during lapses in treatment.¹⁹

Clinical treatment guidelines are available from the Infectious Diseases Society of America.²⁰ See Coccidioidomycosis for a summary.

Coccidioidomycosis therapy can be challenging in persons infected with HIV-1.²¹ Drug interactions between triazoles and antiretrovirals are a concern. The duration of treatment of coccidioidomycosis in those with HIV-1 infection should be either prolonged or life-long. Adherence to antiretroviral therapy may prevent recurrence of coccidioidomycosis. Clinical treatment guidelines for treating opportunistic infections are available from the Centers for Disease Control and Prevention and the Infectious Diseases Society of America for both children with HIV infection and adults and adolescents with HIV infection.^22,23

A clinical trial, POS vs FLU for First Line Treatment of Coccidioidomycosis (Study P04558), is ongoing, but recruiting is complete.

Antifungal agents

Mechanism of action usually involves inhibiting pathways (enzymes, substrates, transport) necessary for sterol/cell membrane synthesis or altering the permeability of the cell membrane (polyenes) of the fungal cell. Fluconazole is most widely used because of its tolerability.^24,25,26

Amphotericin B (Amphocin)

Polyene antibiotic produced by a strain of Streptomyces nodosus; can be fungistatic or fungicidal. Binds to sterols, such as ergosterol, in the fungal cell membrane, causing leakage of intracellular components with subsequent fungal cell death.

Dosing

Adult

0.3-1 mg/kg/d IV; start with 0.25 mg/kg/d and increase by 5-10 mg/d; not to exceed 1.5 mg/kg/d
Severe infections: Start with maintenance dose; not to exceed 1.5 mg/kg/d

Pediatric

Administer as in adults

Interactions

Antineoplastic agents may enhance potential for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; cyclosporine increases risk of renal toxicity

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Monitor renal function, serum electrolytes (eg, magnesium, potassium), liver function, CBC counts, and hemoglobin concentrations; resume therapy at lowest dose (eg, 0.25 mg/kg) when therapy is interrupted >7 d; hypoxemia, acute dyspnea, and interstitial infiltrates may occur in patients who have neutropenia and are receiving leukocyte transfusions (separate administration of amphotericin infusion from leukocyte transfusion); fever and chills not uncommon after first few administrations; rare acute reactions include hypotension, bronchospasm, arrhythmias, and shock

Ketoconazole (Nizoral)

Fungistatic activity. Imidazole broad-spectrum antifungal agent; inhibits synthesis of ergosterol, causing leakage of cellular components and resulting in fungal cell death.

Dosing

Adult

200 mg PO qd; increase to 400 mg PO qd if clinically indicated

Pediatric

<2 years: Not established
>2 years: 3.3-6.6 mg/kg/d PO once

Interactions

Isoniazid may decrease bioavailability; rifampin coadministration decreases effects of either; may increase effect of anticoagulants; may increase toxicity of corticosteroids and cyclosporine (cyclosporine dosage can be adjusted); may decrease theophylline levels

Contraindications

Documented hypersensitivity; fungal meningitis

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Hepatotoxicity may occur; may reversibly decrease corticosteroid serum levels (adverse effects avoided with 200-400 mg/d); administer antacid, anticholinergics, or H2 blockers at least 2 h after administration

Fluconazole (Diflucan)

Fungistatic activity. Synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation, preventing conversion of lanosterol to ergosterol and thereby disrupting cellular membranes.

Dosing

Adult

150 mg PO once or 400 mg qd, depending on severity of infection

Pediatric

3-6 mg/kg PO qd for 14-28 d or 6-12 mg/kg qd, depending on severity of infection

Interactions

Hydrochlorothiazides may increase levels; long-term coadministration of rifampin may decrease levels; coadministration may decrease phenytoin clearance; may increase concentrations of theophylline, tolbutamide, glyburide, and glipizide; coadministration may increase effects of anticoagulants; concurrent administration may increase cyclosporine concentrations

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Adjust dose in renal insufficiency; monitor closely if rashes develop, and discontinue if lesions progress; may cause clinical hepatitis, cholestasis, and fulminant hepatic failure (including death) with underlying medical conditions such as AIDS or malignancy and with multiple concomitant medications; not recommended in breastfeeding

Itraconazole (Sporanox)

Fungistatic activity. Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting cytochrome P-450–dependent synthesis of ergosterol, a vital component of fungal cell membranes.

Dosing

Adult

200 mg PO qd; not to exceed 400 mg/d; increase in 100-mg increments if no improvement (administer >200 mg/d in divided doses)
Alternatively, 200 mg IV bid for 4 doses, followed by 200 mg/d IV
Nail infections: 200 mg/d PO for 3-4 mo or pulse dosing of 400 mg/d PO for 1 wk each mo for 3-4 mo

Pediatric

Systemic fungal infection: 100 mg/d PO

Interactions

Antacids may reduce absorption; edema may occur with coadministration of calcium channel blockers (eg, amlodipine, nifedipine); hypoglycemia may occur with sulfonylureas; high doses may increase tacrolimus and cyclosporine plasma concentrations; rhabdomyolysis may occur with coadministration of HMG-CoA reductase inhibitors (eg, lovastatin, simvastatin); coadministration with cisapride can cause cardiac rhythm abnormalities and death; may increase digoxin levels; coadministration may increase plasma levels of midazolam or triazolam; phenytoin and rifampin may reduce levels (phenytoin metabolism may be altered)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hepatic insufficiency

Follow-up

Further Outpatient Care

• Monitor CF titers after the treatment is completed.
• Increasing titers warrant repeat therapy.
• Lifetime suppression therapy is necessary in patients infected with HIV.

Deterrence/Prevention

• Because coccidioidomycosis cannot yet be prevented in endemic regions, the single most important activity is to develop educational programs for construction and agriculture employees, military personnel, students, and other groups.
• People who live in or visit endemic regions who are also aware of the medical problems that C immitis infection can produce may be more likely to seek medical attention when symptoms arise, resulting in earlier and more effective diagnosis and management.

Complications

• Mycetoma may develop within cavities, either from mycelia due to infection with C immitis or other fungi such as Aspergillus species.
• The rupture of a peripheral coccidioidal cavity into the pleural space is a complication that is most common in young male patients.
• Hydrocephalus is a common complication, especially in children.
• Cerebral vasculitis and focal intracerebral coccidioidal abscesses are less common complications.
• In rare occurrences, an inoculation of C immitis causes primary cutaneous coccidioidomycosis with lymphatic extension to regional lymph nodes; these cases resolve without treatment.
• Approximately 5-10% of infections due to C immitis result in residual pulmonary sequelae.

Prognosis

• In the absence of immunosuppressive disease or therapy, patients with primary pulmonary infections do not need antifungal therapy.
  • The solitary pulmonary nodules resolve by themselves.
  • Moderate and severe cases of airway coccidioidomycosis may be treated with azoles.
• Medical treatment in immunocompromised patients is more challenging. Complete response rates vary from 50-63% in soft tissue and pulmonary infections, and 26-52% in bone or joint infections.
• Coccidioidomycosis infections involving the central nervous system require lifelong suppressive therapy with azoles.
• Coccidioidal meningitis is the most serious form of disseminated infection. Untreated, it is almost always fatal within 2-3 years of diagnosis.

Miscellaneous

Medicolegal Pitfalls

• The failure to provide special laboratory containment facilities for culturing C immitis is a pitfall because of the risk of infecting laboratory personnel with airborne arthrospores
• The failure to prevent the spread of C immitis infection from an osteomyelitis to a plaster cast is a pitfall because airborne arthrospores from such growth pose a substantial risk to hospital personnel.

Special Concerns

• Pregnant women are more likely to acquire disseminated coccidioidal infection, especially in the third trimester or in the immediate postpartum period.
  • A diagnosis of primary infection during the third trimester of pregnancy or in the period immediately after delivery should prompt consideration for treatment.
  • During pregnancy, amphotericin B is the treatment of choice because fluconazole medications, and probably other azole antifungals, are teratogenic.
• Coccidioidomycosis may be imported worldwide from endemic areas. A recent patient in France acquired it during a visit to California.²⁷ A careful travel history is essential.

References

1. Gaidici A, Saubolle MA. Transmission of coccidioidomycosis to a human via a cat bite. J Clin Microbiol. Feb 2009;47(2):505-6. [Medline].

2. Ampel NM, Mosley DG, England B, Vertz PD, Komatsu K, Hajjeh RA. Coccidioidomycosis in Arizona: increase in incidence from 1990 to 1995. Clin Infect Dis. Dec 1998;27(6):1528-30. [Medline].

3. Increase in Coccidioidomycosis - California, 2000-2007. MMWR Morb Mortal Wkly Rep. Feb 13 2009;58(5):105-9. [Medline].

4. From the Centers for Disease Control. Coccidiodomycosis in travelers returning for Mexico--Pennsylvania, 2000. JAMA. Dec 20 2000;284(23):2990-1. [Medline].

5. Wanke B, Lazera M, Monteiro PC, et al. Investigation of an outbreak of endemic coccidioidomycosis in Brazil's northeastern state of Piauí with a review of the occurrence and distribution of Coccidioides immitis in three other Brazilian states. Mycopathologia. Nov 1999;148(2):57-67. [Medline].

6. Cordeiro Rde A, Fechine MA, Brilhante RS, et al. Serologic detection of coccidioidomycosis antibodies in northeast Brazil. Mycopathologia. Apr 2009;167(4):187-90. [Medline].

7. Blair JE. Coccidioidomycosis in liver transplantation. Liver Transpl. Jan 2006;12(1):31-9. [Medline].

8. Ampel NM. Coccidioidomycosis in persons infected with HIV type 1. Clin Infect Dis. Oct 15 2005;41(8):1174-8. [Medline].

9. Arsura EL, Kilgore WB, Ratnayake SN. Erythema nodosum in pregnant patients with coccidioidomycosis. Clin Infect Dis. Nov 1998;27(5):1201-3. [Medline].

10. Spinello IM, Johnson RH, Baqi S. Coccidioidomycosis and pregnancy: a review. Ann N Y Acad Sci. Sep 2007;1111:358-64. [Medline].

11. Woods CW, McRill C, Plikaytis BD, et al. Coccidioidomycosis in human immunodeficiency virus-infected persons in Arizona, 1994-1997: incidence, risk factors, and prevention. J Infect Dis. Apr 2000;181(4):1428-34. [Medline].

12. Buot G, Bachmeyer C, Haettich-Pialoux B, et al. [Coccidioidomycosis revealed by specific cutaneous lesions occurring after placement of a ventricular cardiac shunt for chronic meningitis]. Presse Med. Jun 2008;37(6 Pt 1):970-4. [Medline].

13. Stagliano D, Epstein J, Hickey P. Fomite-transmitted coccidioidomycosis in an immunocompromised child. Pediatr Infect Dis J. May 2007;26(5):454-6. [Medline].

14. Crum NF. Disseminated coccidioidomycosis with cutaneous lesions clinically mimicking mycosis fungoides. Int J Dermatol. Nov 2005;44(11):958-60. [Medline].

15. Sutton DA. Diagnosis of coccidioidomycosis by culture: safety considerations, traditional methods, and susceptibility testing. Ann N Y Acad Sci. Sep 2007;1111:315-25. [Medline].

16. Orsborn KI, Galgiani JN. Detecting serum antibodies to a purified recombinant proline-rich antigen of Coccidioides immitis in patients with coccidioidomycosis. Clin Infect Dis. Dec 1998;27(6):1475-8. [Medline].

17. Bialek R, González GM, Begerow D, Zelck UE. Coccidioidomycosis and blastomycosis: advances in molecular diagnosis. FEMS Immunol Med Microbiol. Sep 1 2005;45(3):355-60. [Medline].

18. Wilde GE, Emery C, Lally JF. Radiological reasoning: miliary disease, vertebral osteomyelitis, and soft-tissue abscesses. AJR Am J Roentgenol. Mar 2008;190(3 Suppl):S11-7. [Medline].

19. Ampel NM, Giblin A, Mourani JP, Galgiani JN. Factors and outcomes associated with the decision to treat primary pulmonary coccidioidomycosis. Clin Infect Dis. Jan 15 2009;48(2):172-8. [Medline].

20. [Guideline] Galgiani JN, Ampel NM, Blair JE, et al. Coccidioidomycosis. Clin Infect Dis. Nov 1 2005;41(9):1217-23. [Medline].

21. Ampel NM. Coccidioidomycosis in persons infected with HIV-1. Ann N Y Acad Sci. Sep 2007;1111:336-42. [Medline].

22. [Guideline] Mofenson LM, Oleske J, Serchuck L, Van Dyke R, Wilfert C. Treating opportunistic infections among HIV-exposed and infected children: recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. Clin Infect Dis. Feb 1 2005;40 Suppl 1:S1-84. [Medline].

23. [Guideline] Mofenson LM, Oleske J, Serchuck L, Van Dyke R, Wilfert C. Treating opportunistic infections among HIV-exposed and infected children: recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. MMWR Recomm Rep. Dec 3 2004;53:1-92. [Medline].

24. Galgiani JN, Catanzaro A, Cloud GA, et al. Comparison of oral fluconazole and itraconazole for progressive, nonmeningeal coccidioidomycosis. A randomized, double-blind trial. Mycoses Study Group. Ann Intern Med. Nov 7 2000;133(9):676-86. [Medline].

25. Koehler AP, Cheng AF, Chu KC, Chan CH, Ho AS, Lyon DJ. Successful treatment of disseminated coccidioidomycosis with amphotericin B lipid complex. J Infect. Jan 1998;36(1):113-5. [Medline].

26. Terrell CL. Antifungal agents. Part II. The azoles. Mayo Clin Proc. Jan 1999;74(1):78-100. [Medline].

27. Chandesris MO, Hot A, Dannaoui E, et al. [Coccidioidomycosis: an imported invasive fungal disease in France]. Med Mal Infect. Jun 2008;38(6):336-42. [Medline].

28. Ampel NM, Hector RF, Lindan CP, Rutherford GW. An archived lot of coccidioidin induces specific coccidioidal delayed-type hypersensitivity and correlates with in vitro assays of coccidioidal cellular immune response. Mycopathologia. Feb 2006;161(2):67-72. [Medline].

29. Awasthi S. Dendritic cell-based vaccine against coccidioides infection. Ann N Y Acad Sci. Sep 2007;1111:269-74. [Medline].

30. Connelly MB, Zerella JT. Surgical management of coccidioidomycosis in children. J Pediatr Surg. Nov 2000;35(11):1633-4. [Medline].

31. Galgiani JN, Ampel NM, Blair JE, et al. Coccidioidomycosis. Clin Infect Dis. Nov 1 2005;41(9):1217-23. [Medline].

32. Goldman M, Johnson PC, Sarosi GA. Fungal pneumonias. The endemic mycoses. Clin Chest Med. Sep 1999;20(3):507-19. [Medline].

33. Kappel ST, Wu JJ, Hillman JD, Linden KG. Histopathologic findings of disseminated coccidioidomycosis with hyphae. Arch Dermatol. Apr 2007;143(4):548-9. [Medline].

34. Larwood TR. Coccidioidin skin testing in Kern County, California: decrease in infection rate over 58 years. Clin Infect Dis. Mar 2000;30(3):612-3. [Medline].

35. Leake JA, Mosley DG, England B, et al. Risk factors for acute symptomatic coccidioidomycosis among elderly persons in Arizona, 1996-1997. J Infect Dis. Apr 2000;181(4):1435-40. [Medline].

36. Long JB, Brett AS, Horvath JA. Coccidioidomycosis diagnosed in South Carolina. South Med J. Sep 2005;98(9):930-2. [Medline].

37. Rosenstein NE, Emery KW, Werner SB, et al. Risk factors for severe pulmonary and disseminated coccidioidomycosis: Kern County, California, 1995-1996. Clin Infect Dis. Mar 1 2001;32(5):708-15. [Medline].

38. Schwartz RA, Lamberts RJ. Isolated nodular cutaneous coccidioidomycosis. The initial manifestation of disseminated disease. J Am Acad Dermatol. Jan 1981;4(1):38-46. [Medline].

39. Yorgin PD, Rewari M, al-Uzri AY, Theodorou AA, Scott KM, Barton LL. Coccidioidomycosis in adolescents with lupus nephritis. Pediatr Nephrol. Jan 2001;16(1):77-81. [Medline].

Keywords

Valley fever, San Joaquin Valley fever, Coccidioides immitis, C immitis, arthroconidia, primary cutaneous coccidioidomycosis, respiratory infection, coccidioidal pneumonia, coccidioidal meningitis

Contributor Information and Disclosures

Author

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Coauthor(s)

Linas Riauba, MD, Assistant Professor of Clinical Medicine, Department of Medicine, Section of Infectious Disease, University Hospital, University of Medicine and Dentistry of New Jersey
Linas Riauba, MD is a member of the following medical societies: American Medical Association and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Medical Editor

Janet Fairley, MD, Professor and Head, Department of Dermatology, University of Iowa
Janet Fairley, MD is a member of the following medical societies: American Academy of Dermatology, American Dermatological Association, American Federation for Medical Research, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Managing Editor

Van Perry, MD, Assistant Professor, Department of Medicine, Division of Dermatology, University of Texas Health Science Center
Van Perry, MD is a member of the following medical societies: American Academy of Dermatology and American Society for Laser Medicine and Surgery
Disclosure: Nothing to disclose.

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

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